ABSTRACT
The mechanisms by which the direct actions of neuroleptics are translated into therapeutic effects are unknown. We immunocytochemically investigated the expression of Fos- and Jun-related proteins and examined activator protein-1 DNA-binding activity in ddY mouse brain 120 min after the administration of haloperidol (1 mg/kg), (-)-sulpiride (20 mg/kg) and a selective dopamine D1 receptor antagonist, SCH23390 (1 mg/kg). The densities of Fos-, FosB-, Fra-1-, Jun- and JunD-immunoreactive nuclei induced by haloperidol and sulpiride in the hippocampus, piriform cortex and accumbens nucleus were higher than those in the control groups. The same regions showed higher densities of FosB-, Fra-1- and JunD-immunoreactive nuclei induced by SCH23390 compared with the control groups. We investigated further the activator protein-1 composite factors using super gel shift assays. These results suggested that induced Fos, FosB, Fra-1, Jun and JunD proteins constitute the activator protein-1 complex after the administration of haloperidol and sulpiride. In contrast, FosB, Fra-1 and JunD appear to constitute the activator protein-1 complex after the administration of SCH23390. Therefore, the diversity of activator protein-1 composite factors suggests that various kinds of gene are induced to act by some neuroleptics.
Subject(s)
Antipsychotic Agents/pharmacology , Brain Chemistry/drug effects , Proto-Oncogene Proteins c-fos/biosynthesis , Proto-Oncogene Proteins c-jun/biosynthesis , Transcription Factor AP-1/biosynthesis , Animals , Benzazepines/pharmacology , Electrophoresis, Polyacrylamide Gel , Haloperidol/pharmacology , Immunohistochemistry , Male , Mice , Nuclear Proteins/metabolism , Sulpiride/pharmacologyABSTRACT
The c-fos and c-jun mRNA expressions were measured by the RNase protection assay method following intraperitoneal injection of haloperidol, (D1 and D2 receptor antagonists), (-)-sulpiride, (D2 receptor antagonist), and SCH23390, (D1 receptor antagonist). Haloperidol and (-)-sulpiride increased their mRNA expressions in a dose-dependent manner, peaking at 30 min after injection followed by a gradual decline. The SCH23390 did not induce expression of either c-fos or c-jun mRNA. A significant decrease of c-fos as well as c-jun mRNA expression was found due to pretreatment with SCH23390 (1 mg/kg i.p.) followed by injection of (-)-sulpiride (20 mg/kg i.p.). The results suggest that the expression of these mRNAs is closely related to the dopamine D2-like antagonism. Administration of haloperidol or (-)-sulpiride increased AP-1 DNA binding activity with similar manner of dose-dependence, whereas their activities were reduced by Fos and Jun antibodies, implying that AP-1 components, transcriptional factors, forming due to Fos and Jun were actually activated by either haloperidol or (-)-sulpiride.
Subject(s)
Benzazepines/pharmacology , Dopamine Antagonists/pharmacology , Haloperidol/pharmacology , Proto-Oncogene Proteins c-fos/biosynthesis , Proto-Oncogene Proteins c-jun/biosynthesis , Sulpiride/pharmacology , Transcription Factor AP-1/metabolism , Animals , DNA/metabolism , Electrophoresis, Polyacrylamide Gel , Image Processing, Computer-Assisted , Male , Mice , Mice, Inbred Strains , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , RNA Probes , RNA, Messenger/biosynthesis , Ribonucleases/metabolismABSTRACT
We encountered a case of small-cell lung cancer in a patient with subacute sensory neuropathy that began 5 months before the cancer was diagnosed. A 60-year-old man complained of abnormalities in the functioning of his peripheral sensory systems (senses of pain, touch, position, and vibration). A chest X-ray film obtained on admission showed an anterior mediastinal tumor. The anti-Hu antibody was found in his serum. The diagnosis was small-cell lung cancer. Combination chemotherapy (cisplatin and irinotecan, CPT-11) was begun and the response was a complete remission. The symptoms of neuropathy continued. The anti-Hu antibody was useful in the diagnosis in the case of small-cell lung cancer combined with subacute sensory neuropathy.
